The present invention relates to the sustained controlled release system constructed by the conjugation of drug molecules with biodegradable polyester polymer, which may be formulated into microspheres, nanoparticles or films, and method for conjugation thereof. According to the system of this invention, the drug release rate can be regulated to be proportional to the chemical degradation rate of the biodegradable polyester polymer, resulting in near zero order kinetic profile of release without showing a burst effect. Moreover, it is possible to achieve the high loading efficiency of hydrophilic drugs in the formulation into microspheres, nanoparticles, or films.
It is difficult to maintain constant drug concentration in blood through the established injection or oral routes of administration. Therefore, in order to maintain constant drug concentration in blood, methods in which a polymer carrier is slowly degraded have been studied for the release of drug in biodegradable polymer carrier at a constant rate [Langer, R., Chem. Eng. Commun., 6, 1-48 (1980); Langer, R. S. and Peppas, N. A., Biomaterials, 2, 201-214 (1981); Heller, J. CRC Crit., Rev. Ther. Drug Carrier Syst., 1(1) 39-90 (1984); Holland, S. J. Tighe, B. J. and Gould, P. L., J. Controlled Release, 155-180 (1986)]. Such a biodegradable polymer carrier system has an advantage that, since the polymer carrier is degraded into low molecular weight molecules, the additional elimination process of the carrier is not needed.
Many kinds of biodegradable polymers have been used as carriers. In general, aliphatic polyester polymers have been frequently used, such as poly(lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid), poly(caprolactone), poly (valerolactone), poly(hydroxybutyrate) and poly (hydrovalerate), etc. [Peppas, L. B. International journal of pharmaceutics, 116, 1-9 (1995)]. In particular, poly(D-lactic-co-glycolic-acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid) (hereinafter, generically refered to as poly(D/L-lactic-co-glycolic acid) have been widely used. It was ascribed that biodegradable polymers with various life spans of degradation could be produced and drug release could be regulated for weeks or years, by controlling the molar composition ratio of monomer comprised of lactic acid and glycolic acid or controlling the molecular weight of the polymer.
However, formulations comprising drugs and aliphatic polyester polymers as carriers have had some difficulties in controlling the rate of drug release over a desired period due to an initial burst effect. This resulted from the fact that drug release is not dependent on the polymer erosion process but on the diffusion of drug. Particularly, this problem is serious for hydrophilic drugs such as peptides or proteins. For example, microspheres or films consisting of gentamycin sulfate and polyester polymer carrier were observed to show the initial burst effect. Also, it was reported that hydrophilic gentamycin compound had initial burst effects over 50% [Mauduit, J., Bukh, N., and Vert. M., J. Controlled release, 23, 209-220 (1993); Mauduit, J., Bukh, N., and Vert. M., J. Controlled release, 23, 221-230 (1993); Mauduit, J., Bukh, N., and Vert. M., J. Controlled release, 25, 43-49 (1993)] and neurotensin analog over 20% [Yamakawa I., Tsushima, Y., Machida, R., and Watanable, S., J. Pharma. Sci., 81, 808-811 (1992)]. To solve such a problem, there have been efforts to develop new methods for manufacturing various microspheres, nanoparticles and films [Peppas, L. B. International journal of pharmaceutics, 116, 1-9 (1995)].
Biodegradable, biocompatible matrices for drug delivery including microspheres, nanoparticles, and films have been widely used for an injectable depot formulation of various small molecular weight drugs, peptides, and proteins which required multiple administrations. It has been known that drug release kinetic rate from the microspheres, nanoparticles, and films is determined by diffusion and/or polymer erosion process [D. D. Lewis, et al, in Biodegradable Polymers as Drug Delivery System, in M. Chasin and R. Langer (Eds.), Marcel Dekker, New York (1990) pp. 1-41]. For small diameter microspheres and nanoparticles as an injectable dosage form, it has been difficult to predictably control the drug release kinetic rate over a desired period due to an initial burst effect combined with the process of relatively faster diffusion of the drug than the erosion of the matrices. This problem is particularly acute for hydrophilic drugs that are believed to exist in pre-formed microporous aqueous channels within the microspheres [S. Cohen, et al., Pharm. Res. 8 (1991) 713-720].
The most common method of preparing microspheres and nanoparticles for hydrophilic drugs is a double emulsion solvent evaporation technique which adopts a two phase emulsion system composed of polymer dissolved organic phase containing primary aqueous emulsion droplets as a dispersed phase and a continuous phase of water [Y. Ogawa, et al., Chem. Pharm. Bull. 36 (1988) 2576-2588]. This method inevitably generates porous morphology in the microspheres and nanoparticles matrices, leading to burst and very fast release kinetics of the hydrophilic drugs through pre-existing macro- and micro-pores. For hydrophobic drugs, a single oil-in-water emulsion system has been employed to prepare drug loaded microspheres and nanoparticles. In this case, drug release kinetic rate was mainly controlled initially by diffusion through existing pores and later by polymer erosion process, resulting in a triphasic release profile. Most of previous studies for controlled release of hydrophilic drug from biodegradable polyester microspheres and nanoparticles, however, could not achieve a zero order release profile over an extended period because of complicated nature of drug release mechanism, that is, a diffusion coupled polymer erosion process (H. T. Wang, et al., J. Controlled. Release 17 (1991) 23-32].
On the other hand, a new drug delivery system has been developed through conjugating a synthetic polymer to a drug via a covalent bond or by modifying the biodegradable polymer. For example, the system developed by conjugating drug with polyethylene glycol(hereinafter, refered to as PEG) approved by FDA, which is hydrophilic, linear, and non-immunologic polymer, was reported to increase circulation time of the drug in blood stream [Zhu, K. J., XiangZhou, L. and Shilin, Y. J. Appl. Polym. Sci. 39, 1-9 (1990; Davis, F. F., Kazo, G. M., Nucci, M. L., and Abuchwski, A., In Lee, V. H. L.(Ed.), Peptide and Protein Drug Delivery, Dekker, New York, 831-864 (1991)]. PEG has been applied to many drugs. At least six classes of PEG-enzyme comlexes, including PEG-adenosine amylase, PEG-antigen, PEG-asparaginase, and PEG-uricase, are under the clinical trials or approved by FDA.
Recently, anti-cancer drugs have been chemically conjugated to various polymers for the purpose of their efficient passive targeting to solid tumors [R. Duncan, et al., Anti-cancer Drugs, 3:175-210 (1992), H. Maeda, et al., J. Med. Chem, 28: 455-461 (1985), T. Minko, et al., J. Control Release, 54: 223-233 (1998)]. The xe2x80x9cenhanced permeation and retention (EPR)xe2x80x9d effect on the site of tumor capillaries plays a critical role in accumulating the polymer conjugates in the solid tumors, while minimizing the glomerular excretion rate [H. Maeda., et al., CRC Crit. Rev. Ther. Drug Carrier Sys., 6: 193-210 (1989), L. W. Seymour, et al., CRC Crit. Rev. Ther. Drug Carrier Sys., 9: 132-187 (1992)]. Water soluble polymer conjugates based on poly(N-(2-hydroxypropyl)methacrylamide) have been extensively studied and are now under clinical trials [V. Omelyanenko, et al., J. Control Release, 53: 25-37 (1998)]. Another promising approach is to conjugate doxorubicin to an amphiphilic block copolymer composed of polyethyleneglycol (PEG) and poly(xcex1,xcex2-aspartic acid), which leads to a polymeric micelle structure [M. Yokoyama, et al., Bioconjugate Chem. 3: 295-301 (1992)]. Besides the above two examples, doxorubicin has been physically adsorbed onto and/or encapsulated within nondegradable and biodegradable nanoparticles [J. Leroux, et al., Microencapsulation: Methods and Industrial Applications, S. Benita Ed., Marcel Dekker, New York, 535-576 (1996), P. Couvreur, et al., J. Control. Rel., 17: 187-198 (1991)], protein nanoparticles [Y. Morimoto, et al., Chem. Pharm. Bull., 29: 1433-1439 (1981)], and liposomes [A. A. Gabizon, et al., Pharm. Res., 10: 703-708 (1993)., K. Yachi, et al., Biopharm. Drug Dispos., 16: 653-667 (1995).]. The above doxorubicin formulations intend to achieve passive targeting of doxorubicin loaded particles to the tumor site.
The recent approach indicates that if the conjugation of a drug with biodegradable polyester is applied to the formulation of nanoparticles, this technique will provide not only the aforementioned advantages such as high loading efficiency and zero order release kinetics but also the passive targeting of the anticancer drugs to solid tumors.
In accordance with the present invention, there is provided a novel sustained controlled release system constructed by conjugation of molecules to be released with biodegradable polyester polymers.
In particular, the present invention provides a sustained controlling-release system with high loading efficiency of drug molecules.
The present invention also provides the sustained controlled release system formulated into either microspheres, preferably about 1 to about 300 xcexcm in diameter, nanoparticles, preferably about 50 to about 1000 nm in diameter, or films.
In addition, this invention provides the sustained controlled release system using a biodegradable polyester polymer selected from the groups comprising poly(lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid), poly(caprolactone), poly(valerolactone), poly(hydroxybutyrate), poly(hydrovalerate), polydioxnanone, and derivatives thereof. More preferably, the biodegradable polyester polymer is about 1,000 Da to about 100,000 Da in molecular weight.
This invention additionally provides the system using poly(lactic-co-glycolic acid) as a biodegradable polyester polymer with various compositions, wherein the preferred ratio of lactic acid and glycolic acid, from 1:10 to 10:1.
This invention provides the system employing the ester bond, amide bond, anhydride bond, urea bond, urethane bond, carbonate bond, imine bond, thioester bond, disulfide bond or carbamate bond for conjugation of molecules with biodegradable polyester polymers.
This invention also provides the system wherein the specified moieties are either directly bound to one another through covalent bond, or else indirectly bound to one another with an additional moiety such as a bridge, spacer, or linkage moieties.
Additionally, this invention provides the system wherein the molecules to be loaded are selected from the groups comprising peptides, proteins, therapeutic agents, diagnostic agent, and non-biological materials such as pesticides, herbicides, and fertilizers.
This invention also provides a process of preparing the sustained controlled release system, comprising the steps of;
1) activating A drug molecule or polymer by mixing with coupling agents, bases, and, if needed, additives;
2) conjugating the drug molecule with the polymer by adding the drug molecule to the activated polymer solution of step 1, or by adding polymer to the activated drug molecule solution of step 1;
3) purifying polymer-molecule conjugate of step 2.
Accordingly, an object of the present invention is to provide biodegradable polyester polymer-drug conjugates formed via covalent bond.
Another object of the present invention is to provide biodegradable polyester polymer-drug conjugates having an advantage that the removal process of the polymer carrier is not required after drug release, as a result of polymer degradation into low molecular weight molecules.
Still another object of the present invention is to provide microspheres, nanoparticles or films that are easy to formulate from biodegradable polyester polymer-drug conjugates by a single oil in water emulsion method.
Yet another object of the present invention is to provide microspheres, nanoparticles and films with high loading efficiency of hydrophilic drug.
A further object of the present invention is to provide a sustained controlled release system wherein the initial burst of molecules is prevented and zero order release profile is achieved by controlling the molecule release rate in accordance with the chemical degradation rate of the biodegradable polymer.